The use of drugs or other agents for destroying or inflicting permanent damage on living cells serves a number of valuable and legitimate objectives. A major clinical use is for the ablation of malignant tumors or other abnormal tissue growths. V T DeVita, Jr., IN: Cancer, Principles and Practice of Oncology, 4th ed., pp. 276-292, JB Lippincott Co. Philadelphia (1994).
Other valuable clinical uses have included (1) medical control of abnormal immunologic reactions, K Wilson et al., Rheumatol. 21:1674-7 (1994); C M Neuwelt et al., Am. J. Med. 98:32-41; (1995); (2) exfoliative dermatological disease, G D Weinstein et al., J. Am. Acad. Dermatol. 28:454-9 (1993), R J Van Dooren-Greebe et al., Br. J. Dermatol. 130:204-10 (1994); (3) killing of cells infected by viruses, viral replicative elements, or prions, P Calabresi et al., Section XII--Chemotherapy of neoplastic diseases IN: Goodman and Gilman's The; Pharmacologic Basis of Therapeutics, 8th ed., 1202-1263 (Pergammon Press, New York 1990):, S Chou et al., Antiviral chemotherapy, Chapter 17 IN: Virology, pp. 323-348, ed. B N Field; et al., Raven Press, New York (1985); (4) therapies for systemic or topical elimination of infective agents including bacteria, mycobacteria, mycoplasma, rickettsia, fungi, yeast, or parasitic organisms, H P Willett, The action of chemotherapeutic agents, Chapter 10, IN: Zinsser Microbiology, 17th ed., pp. 234-277, ed. Joklik et al., Appleton-Century-Crofts, NY (1980); Lorian, Antibiotics in Laboratory Medicine, 3d ed., Williams and Wilkins, Baltimore (1991); S Sternberg, Science 266:1632-1634 (1994), (5) and fertility control. Nonclinical uses cf agents capable of inflicting permanent damage on living cells occur in agriculture, horticulture, or public health, e.g., application of specific pesticides or herbicides.
A vast array of physical, chemical, or biological agents are hazardous to living cells and can inflict damage upon biological systems such as tissues or organs. In many cases, however, the damage is not specifically targeted to events related to the cell-division cycle.
In other cases, cell damage may be initiated in direct relation to the hierarchy of the cell-division cycle. A cytotoxic agent that acts during some portion of the cell-division cycle, causing biologically significant or irreversible damage to a proliferating cell, may serve as a "targeted cytotoxic insult" or "TCI", as defined herein. The portion of the cell-division cycle during which a given TCI initiates a relevant action is its "target interval."
Known agents that can act as TCIs are diverse and include natural substances, products of microbial or other cellular origins, synthetic or semi-synthetic organic or inorganic chemical compounds, or simple inorganic reagents. Other factors that can act as a TCI are also known and may include deprivation of nutrients essential to cell growth or sustenance as well as changes in the physicochemical environment. Examples of the latter include temperature changes and exposure of the cells to radiant or particulate energies, vibrational waves, or various other physical forces.
Cytotoxic effects of a TCI may not be immediate, so that cell damage initiated in one phase of the cell-division cycle may not become manifest until a later phase or a subsequent cell cycle. As just one example, in cisplatin treatment, permanently injured progeny cells may be sterile or exhibit a reduced capacity to proliferate or survive. M Sorenson, J Natl. Cancer Inst. 82:749-55 (1990). Thus, an understanding of the cell-division cycle hierarchy becomes useful to further understanding of agents that can act as TCIs.